Why hasn't Stem Cell Therapy Work For Me?
When a patient questions or comes into our office seeking answers to why stem cell therapy did not work for their knee pain, we suggest that perhaps the answer was NOT:
- Because autologous blood stems cells were used when bone marrow stem cells should have been used or vice versa.
- or even Because the number of stem cells were inadequate.
It may be that the stem cell therapy has not yet had a chance to work because it has not been given the full chance to work. This may be a difficult idea for patients to understand, so here we will discuss why stem cell therapy may not have had the desired outcome yet for a patient with knee arthritis, and what we believe we can do to give it its best chance of working.
There are many reasons why we develop degenerative joint arthritis, physically stressful job, high level of activities, even including past histories of arthroscopic surgeries.
The main factor however is that the osteoarthritic joint is degenerating faster than the body can repair it. The body’s healing response is inflammation. Inflammation will turn on and continue staying on until the joint is healed. But what if the joint does not heal because the injury is too severe for the body to heal on its own? Then the inflammatory mechanism will be stuck in the “open” position, chronic inflammation will continue trying to heal something it can’t-referred to as 'runaway inflammation'.
A Chondrocyte is a cell that makes cartilage.
When you have many chondrocytes doing the same thing, they create a healing environment of positive, healing inflammation. This is what cartilage regeneration is, repair cells acting in a positive inflammation environment. But, when the chondrocytes can not complete the repair, it cannot shut off the inflammation, the inflammatory loop creates a toxic environment of oxidative stress. The stress factors create a diseased environment.
Stem cells do have the the ability to change this degenerative toxic environment into a regenerative healing environment. When stem cells are injected into a diseased joint they start talking to the repair cells, the blood cells, the inflammatory cells, and the native stem cells in a “reboot” command to restart the natural healing of the joint. This comes under the phenomena of “cell signalling".
However, the stem cells can be bogged down and the messages blurred by the oxidative stress caused by the chronic inflammation, so repair can take longer and be more challenging. It is this issue which becomes the greatest hurdle for any regenerative medicine practitioner.
While adult stem cells may be a promising cell source for cartilage regeneration, increasing evidence indicates that environmental preconditioning is a powerful approach in promoting stem cells’ ability to resist a harsh environment where the cells are in a constant oxidative state. So, even if the practitioner's intentions are 'pure' of heart, putting them into such an environment gives them little to no chance of survival.
The idea is to get the stem cells ready to more efficiently heal by changing their conditioning and the joint environment by removing oxidative stress in the joint.
An inflammatory milieu breaks down the cartilage matrix and induces chondrocyte apoptosis, resulting in cartilage destruction in patients with cartilage degenerative diseases, such as rheumatoid arthritis or osteoarthritis. Because of the limited regenerative ability of chondrocytes, defects in cartilage are irreversible and difficult to repair. Mesenchymal stem cells (MSCs) are expected to be a new tool for cartilage repair because they are present in the cartilage and are able to differentiate into multiple lineages of cells, including chondrocytes. Although clinical trials using MSCs for patients with cartilage defects have already begun, its efficacy and repair mechanisms remain unknown.
Figure 1
The inflammatory milieu is known to cause cartilage destruction by causing disturbances in the anabolic/catabolic balance of the cartilage matrix. The inflammatory milieu has also been understood to exert a suppressive action during the process of differentiation from progenitor MSCs to chondrocytes. Therefore, sufficient suppression of articular inflammation prior to a procedure may be important for efficient regeneration of the cartilage in regenerative therapies using MSCs. While continuous studies to develop more efficient techniques for chondrogenic differentiation using MSC-based cell therapies are important, it is necessary to establish a protocol for the improvement and maintenance of the intra-articular environment, where MSCs are transferred, to be suitable for cartilage regeneration.
In several clinical trials(12), MSCs injected into the joints by the least-invasive intra-articular method, and were expected to differentiate into chondrocytes locally in the joint. Whether or not the intra-articular environment of the joints was suitable for chondrogenic differentiation of MSCs is a major concern. As mentioned , cartilage regenerative therapy is likely to be indicated when the affected joints in patients with OA and RA present with inflammatory reactions. However, the inflammatory milieu, including proinflammatory cytokines, strongly inhibits MSC differentiation into chondrocytes. On the other hand, it has been demonstrated that the influence of inflammation (pro inflammatory cytokines) on MSC is differentiation into osteoblasts, resulting in the formation of calcifications. These findings may indicate the risk of developing osteophytes and ectopic calcifications when MSCs are injected into the joint in an inflammatory milieu. Therefore, sufficient suppression of articular inflammation prior to any procedure is important for efficient cartilage regeneration while using MSCs in cartilage regenerative therapy. This can be achieved by a combination of an existing anti-inflammatory agent or a biologic targeting proinflammatory cytokine and a chondro-enhancing agent (Figure 1).